Kasper C., van Griensven M., P?rtner R. (Eds.) Bioreactor Systems for Tissue Engineering II: Strategies for the Expansion and Directed Differentiation of Stem Cells
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cells [104] and, thus, might be the long sought source not only for T1D disease
modeling but also for future cell replacement therapies.
8 Induced Pluripotent Stem Cells for Cell-Based Therapies
The above-mentioned iPS cells from T1D provide a good example for the two
aspects of iPS cell research in regenerative medicine. Besides indirect use of iPS-
cell derivatives to study pathophysiology and new pharmacotherapeutic strategies
of the respective disorder, patient-specific iPS cells would be a unique resource as
therapeutic cell transplants if mature and functional cell derivatives were obtainable
by in vitro differentiation. According to the efforts of various laboratories as well as
of the company Novocell Inc., it might well be that b-cells from diabetic patients’
iPS cells are the first autologous iPS-derivatives to be used in clinical applications.
Hereby, one major concern reflects autoimmunologic depletion of the patients’ iPS
cell-derived cel l transplant, which might be overcome by encapsulation of the
transplanted cells into alginate-based matrice s [105].
Again, the first proof-of-principle for iPS cell-based therapies was given in the
field of hematology using a humanized sickle cell anemia mouse model. After
generation of iPS cells from these mice, the autologous iPS cells could be geneti-
cally repaired by correction of the human sickle hemoglobin allele applying gene-
specific targeting. Moreover, by in vitro differentiation, disease-free hematopoietic
progenitor cells could be obtained, which were able to ameliorate the phenotype
after transplantation into the diseased mice [106].
Even if therapeutic applications with human iPS cells need to overcome various
technical and safety issues, a lot of other diseases could be candidates for iPS-
derived cell therapies. However, besides safety issues while generating iPS cells,
one might also take into account that some genetic disorders will require genetic
correction of the primary donor cells prior to iPS reprogramming. This was the case
when Raya and collea gues from Belmonte’s lab [107] were attempting to generate
iPS cells from patients suffering from Fanconi anemia (FA). Due to the chromo-
somal instability of the primary FA-fibroblasts the authors were unsuccessful in
generating FA-specific iPS cells. Only cells that were corrected using a normal
copy of the FANCA gene gave rise to iPS cell lines that could be expanded and pass
all criteria for human pluripotent stem cells. Furthermore, these cells did not show
major abnormalities during in vitro hematopoiesis, suggesting their future use in
therapeutic applications once the above-mentioned safety issued are sufficiently
resolved.
As mentioned above, human iPS cell-derived hepatic cells can be obtained if
suitable differentiation protocols are applied [94, 95]. Besides their use for pharma-
cologic applications such as drug screening and toxicological analyses, hepatic iPS-
cell derivatives might become a valuable autologous source for cell therapies of
acute liver failure or of metabolic liver diseases. However, refined differentiation
protocols need to be established that result in a more mature hepatic phenotype,
118 T. Cantz and U. Martin
which can efficiently engraft and repopulate diseased livers. As pointed out in a
recent study taking advantage of a murine competitive liver repopulation assay,
human ES cell-derived hepatic cells failed to give rise to a detectable amount of
hepatic cells in this xeno-transplantation model [108].
Innovative concepts in treating retinal degeneration focus on stem cell-derived
photoreceptor progenitor cells or retinal pigmented epithelial cells. In a recent
study, Osakada et al. describe the generation of retinal progenitor cells from both
human ES cells and human iPS cells, using a small molecule-based differentiation
protocol that avoids cross-species contaminations as observed if bacterial or animal
products were used [109]. Su ch xeno-free iPS cell-derived retinal progenitors may
be highly useful for clinical translation of therapeutic concepts as developed by
Lamba and colleagues, who transplanted human iPS-derived retinal epithelial cells
into mice and were able to demonstrate engraftment of human cells in the mouse
retina and show expression of photoreceptor markers [110].
Whether finally patient-specific iPS cells or allogeneic iPS will be clinically
applied is not clear at present. Certainly, autologous cel ls are advantageous since
pharmacological immunosuppression is not required. However, if patient-specific
iPS-derivatives are applied, the required time frame for isolation and culture of
primary cells, reprogramming, selection of suitable clones, expansion, differentia-
tion, enrichment, and optionally tissue engineering has to be considered and will
exclude treatment of acute diseases and injuries. Maybe worldwide banking of
allogeneic iPS(-derivatives) may provide the required cells at least for the majority
of patients. Other possibilities are the engineering of genetically modified “univer-
sal” cell lines or the development of clinically applicable iPS-based tolerance
induction protocols. In both cases, cell production would be possible on an indus-
trial scale, thereby leading to dramatically reduced costs compared to autologous
cell therapy.
9 Perspectives
The generation of human iPS cells [6, 8, 111 ], together with the latest developments
showing production of iPS cells without integrating vectors [69 –71, 75], create new
opportunities for the establishment of clinically useful autologous stem cell lines
(Fig. 1).
After these pioneering developments, four major issues need to be addressed. First,
it is now crucial to develop technologies that enable selection of the “best” ones from
the large number of iPS clones that usually result from one reprogramming experi-
ment: besides culture characteristics, the potential for teratoma formation and poten-
tial predetermination to differentiate in the desired lineage(s) are critical for clinical
application. Second, it is mandatory to improve the efficiency and specificity of
in vitro differentiation in order to obtain iPS-cell derivatives that are mature enough
to mimic the targeted (diseased) cell type during drug screening and toxicology
analyses. Third, besides differentiation strategies, functional engraftment capabilities
Induced Pluripotent Stem Cells: Characteristics and Perspectives 119
of transplanted human iPS-cell derivatives need to be addressed. Finally, and
probably most critical, several safety issues need to be resolved, because the iPS
cells themselves and their different iated derivatives might harbor various genetic
and epigenetic abnormalities, which could be acquired just during the reprogram-
ming process or selected during expansion of the (most proliferative) cell clones.
In conclusion, iPS cell biology is a young field within stem cell research that
covers various important and attractive scientific areas, ranging from basic under-
standing of (epi-)genetics during nuclear reprogramming, over applied sciences
with respect to stem cell expansion and differentiation, to translational research on
clinical applications in (large) animal models in preparation for future phase-I
clinical trials.
Acknowledgments We are very grateful to the members of our labs for providing intensive
discussions and a lot of critical input, which contributed to this review. Both authors are group
leaders within the cluster of excellence REBIRTH (REgenerative BIology and Reconstructive
THerapy), which is funded by the German Research Foundation (DFG; EXC 62/1). Further
funding is provided by the DFG (MA 2331/6-1, SCHO 340/4-1), the Federal Ministry of Education
and Research through grants 0313926A, 01GN0812, 01GN0816 and 01GM0854, 01GN0958 and
0315493, as well as by the Jose
´
Carreras leukemia foundation (DJCLS R09/01).
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DOI: 10.1007/10_2010_72
#
Springer-Verlag Berlin Heidelberg 2010
Published online: 10 June 2010
Induced Pluripotent Stem Cell Technology
in Regenerative Medicine and Biology
Duanqing Pei, Jianyong Xu, Qiang Zhuang, Hung-Fat Tse,
and Miguel A. Esteban
Abstract The potential of human embryonic stem cells (ESCs) for regenerative
medicine is unquestionable, but practical and ethical consideratio ns have ham-
pered clinical application and research . In an attempt to overcome these issues, the
conversion of somatic cells into pluripotent stem cells similar to ESCs, commonly
termed nuclear reprogramming, has been a top objective of c onte mpor ary biology.
More than 40 years ago, K ing, Briggs, and Gurdon pioneered somatic cell nuclear
reprogramming in frogs, and in 1981 Evans s uccessfu lly isolated mouse ESCs.
In 1997 Wilmut and collaborators produced the first cloned mammal using
nuclear transfer, and then Thomson obtained human ESCs from in vitro fertilized
blastocysts in 1998. Over the last 2 decades we have a lso seen remarkable findings
regarding how ESC behavior is controlled, the importance of which should not be
underestimated. This knowle dge allowed the laboratory of Shinya Yamanaka to
overcome brilliantly conceptual and technical barriers in 2006 and generate
induced pluripotent stem cells (iPSCs) from mouse fibroblasts by over expressing
defined combinations of ESC-enriched tr anscription factors. Here, we discuss
some impor tant implications of human iPSCs for biology and medicine and also
point to possible future directions.
Keywords Disease modeling, Embryonic stem cells, Induced pluripotent stem
cells, Regenerative medicine, Reprogramming
D. Pei (*), J. Xu, Q. Zhuang, and M.A. Esteban (*)
Stem Cell and Cancer Biology Group, Key Laboratory of Regenerative Biology, South China
Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine
and Health, Chinese Academy of Sciences, Guangzhou 510530, China
e-mail: esteban@gibh.org, pei_duanqing@gibh.ac.cn
H.-F. Tse
Cardiology Division, Department of Medicine, University of Hong Kong, Hong Kong, China